3,3-dihydroxy-5-aryl-1h-1,5-benzodiazepine-2,4-(3h,5h)-diones and their anhydrous 2,3,4-trione form

ABSTRACT

Compounds of the formula   WHEREIN R1, R2 and R3 have the meanings defined above; the   compounds are useful as tranquilizers and anticonvulsives,   also as intermediates for the preparation of other 1H-1,5-   benzodiazepine-2,4-(3H,5H)-diones.   WHEREIN R1 is hydrogen, straight or branched alkyl of one to four carbon atoms, omega -hydroxy-(alkyl of one to four carbon atoms) or allyl, R2 is phenyl, halo-phenyl, hydroxy-phenyl, trifluoromethylphenyl, nitro-phenyl or pyridyl, and R3 is fluorine, chlorine, bromine, trifluoromethyl or nitro, AND THEIR ANHYDROUS 2,3,4-TRIONE ANALOGS OF THE FORMULA   WHEREIN R1, R2 and R3 have the meanings defined above; the compounds are useful as tranquilizers and anticonvulsives, and also as intermediates for the preparation of other 1H-1,5benzodiazepine-2,4-(3H,5H)-diones.

United States Patent [191 Bauer et al.

[ 51 Jan. 16,1973

Jan. 26, 1972 [22] Filed:

[21] Appl. No.: 221,072

[30] Foreign Application Priority Data I Jan. 27, 197i Germany ..P 21 03744.5

[52] US. Cl. ..260/239.3 B, 424/244, 424/263 [51] Int. Cl. ..C07d 53/0458 Field of Search,..., ..260/239.3B

[56] References Cited UNITED STATES PATENTS 3,660,381 5/1912 Weberetal.......'260/239.3B

Primary Examiner--l-lenry R. Jiles Assistant Egcqninerg-Robert T. BondAttorney-Nelson Littell et al [57 ABSTRACT Compounds of the formula ft-0:0 OH

N-C=O H wherein R is hydrogen, straight or branched alkyl' of one tofour carbon atoms, m-hydroxy-(alkyl of one to four carbon atoms) orallyl, v R is phenyl, halo-phenyl, hydroxy-phenyl,

trifluoromethyl-phenyl, nitro-phenyl or pyridyl,

and R is fluorine, chlorine, bromine, trifluoromethyl or nitro, andtheir anhydrous 2,3,4-trione analogs of the formula wherein R R and Rhave'the meanings defined above; the compounds are useful astranquilizers and anticonvulsives,. and also as intermediates for thepreparation of other lH-l,5-benzodiazepine-2,4-

[3H,5H1-diones. v

6 Claims, No Drawings 3 ,3-DIHYDROXY-5-ARYL-Ill-1,5-BENZODlAZEPINE-2,4-(3H,5H)-DIONES AND THEIR ANHYDROUS 2,3 ,4-TRIONE FORMThis invention relates to novel 3,3-dihydroxy-5-aryllH-l,5-benzodiazepine-2,4-[ 3H,5l-l]-diones and their anhydrous2,3,4-trione analogs, as well as to methods of preparing thesecompounds.

More particularly, the present invention relates to a novel class ofcompounds represented by the formula wherein R, is hydrogen, straight orbranched alkyl of one to four carbon atoms, w-hydroxy-( alkyl of one tofour carbon atoms) or allyl,

R is phenyl, halo-phenyl, hydroxy-phenyl, trifluoromethyl-phenyl,nitro-phenyl or pyridyl, and

R is fluorine, chlorine, bromine, trifluoromethyl or nitro,

and their anhydrous 2,3,4-trione analogs of the formula f -C=O i is R I1 wherein R,, R and R have the meanings defined above.

The compounds embraced by formula I may be prepared by the followingmethods:

Method A By strong oxidation of a 3-(amino-methylidene)-lH-l,5-benzodiazepine-2,4-[3H,5H]-dione of the formula wherein R,, R and Rhave the same meaningsv as in formula I and R, and R are each hydrogenor straight or branched alkyl of preferably one to four carbon atoms, inthe presence of an inert organic solvent, such as acetone,dimethylformamide or dimethylsulfoxide, at a temperature between roomtemperature and the boiling point of the particular solvent which isused, and with an oxidizing agent, such as potassium permanganate orchromic acid.

The starting compounds of the formula ll required for this method and aprocess for their preparation are disclosed in the copending applicationSer. No. 221,046 of Karl-Heinz Weber, Adolf Bauer, Peter Danneberg,Klaus Minck and Karl-Heinz Pook entitled 2 1,5,7-Trisubstituted-3'-Hydroxyll-l-l ,5-Benzodiazepine-2,4-[3H,5Hl-Diones filed on Jan. 26, i972.

The process disclosed in said copending application comprises reacting acorrespondingly 5,7-disubstitutedlH-l,5-benzodiazepine-2,4-[3H,5H]-dione with a phosphorus pentahalideand a dialkylformamide, which yields a compound of the formula IIwherein R, is hydrogen. Therefore, if it is desired to prepare acompound of the formula I wherein R, is other than hydrogen by thepresent method, it is necessary to introduce the desired l-substituenteither before or after the oxidation pursuant to conventional alkylationprocedures.

Method B By oxidizing a 3-hydroxy-lH-l,S-benzodiazepine-2,4-[3H,5l-l]-dione of the formula wherein R,, R, and R, have the samemeanings as in formula I, with an oxidizing agent, such asseleniumdioxide, manganese dioxide, chromic acid or potassiumpermanganate, in the presence of an inert organic solvent, such asdimethylformamide, dimethylsulfoxide or acetone, at a temperaturebetween room temperature and the boiling point of the particular solventwhich is used..

The starting compounds of the formula lll require for this method andprocesses for their preparation are also disclosed in the copendingapplication referred to above.

The end products obtained pursuant to methods A and B are 3,3-dihydroxycompounds corresponding to formula I; they are the hydrate form of thecorresponding 2,3,4-trione compounds of the formula la.

A compound of the formula I may readily be converted into thecorresponding compound of the formula la by conventional dehydrationmethods, such as by subjecting the former to a high vacuum, optionallyat moderately elevated temperatures, for several hours.

In those instances where methods A and B yield a compound of the formulain wherein R, is hydrogen, this compound may, if desired, be selectivelyalkylated in accordance with conventional methods, for instance by firstforming the corresponding l-alkali metal salt and then reacting thissalt with a conventional alkylating agent, suchas an alkyl halide or adialkyl sulfate.

Likewise, in those instances where methods A and B yield a compound ofthe formula la wherein R, is hydrogen, a hydroxyalkyl group may beintroduced into the l-position by reacting the l-unsubstituted compoundwith a corresponding alkyleneoxide in the presence of a strong base,such as a methanolic 35 percent solution of benzyl trimethylammoniumhydroxide (Triton B), and optionally of a suitable inert solvent medium,such as a lower alkanol, tetrahydrofuran, dimethylformamide, mixturesthereof or aqueous mixtures thereof. Another method of introducing ahydroxyalkyl group in the l-position of a compound of the formula lawherein Ris hydrogen consists of reacting the latter with acorresponding halo-alkanol in the presence of a weak inorganic ororganic base, preferably at elevated temperatures; under certaincircumstances thepresence of an organic solvent, such as an alkanol, isadvantageous. 1

By means of the above-described methods the following end products ofthe formula I and their anhydrous 2,3,4-trione analogs may be obtained:7-Chloro-3 ,3-dihydroxy--phenyl-1H-l,5-benzodiazepine-2,4-[3H,5l-l]-dione, 7-Bromo-3,3-dihydroxy-5-phenyll H- l,5- benzodiazepine-2,4-[3H,5H]-dione, 3,3-Dihydroxy-S-phenyl-7-trifluoromethyl-1H-1,5-

benzodiazepine-2,4-[3H,5l-l]-dione, 3 ,3-Dihydroxy-7-nitro-5-phenyl- 1H-l ,5-

benzodiazepine-2,4-[3H,5l-l]-dione, 7-Chloro-5-( o-fluoro-phenyl )-3,3-dihydroxy-1H- l,5-benzodiazepine-2,4-[3H,5H l-dione,7-Bromo-3,3-dihydroxyl -methyl-5-phenyll H-l ,5-

benzodiazepine-2,4-[3H,5H]-dione, 3 ,3-Dihydroxyl-methyl-5-phenyl-7-trifluoromethyllH-l ,5-benzodiazepine-2,4-[ 3H,5H]-dione, 7-Chloro-3,3-dihydroxy-l methyl-5-(otrifluoromethyl-phenyl)- lH-l ,S-benzodiazepine- 2,4-[3H,5H]-dione, 5 o-Chloro-phenyl )-3,3-dihydroxyl -methyl-7- a qqxsam thy r H1 5- n29diz r2 .n-2A;[

3H,5H]-dione, I S-(p-Chloro-phenyD-B ,B-dihydroxy- 1-methyl-7 -l i- -b!!AQ 2z n2:2,4-I r ii H HPdio'ne,

7-Bromo-3,3-dihydroxy-5-(o-fluoro-phenyl)-1- methyl- 1 H- l,5-benzodiazepine-2,4-[ 3H,5H dione,

3,3-Dihydroxy-5-(p-hydroxy-phenyl)-l-methyl-7- trifluoromethyll H-l,5-benzodiazepine-2,4-[

3,3-Dihydroxy-l-methyl-5-(o-nitro-pheny|)-7- trifluoromethyll'H-l,5-benzodiazepine-2,4-[3H,'5H13,3-Dihydroxy-l-methyl-S-(mnitro-phenyl)-7-trifluoromethyll H- l,5- benzodiazepine-2,4-[3H,5H]-dione,

' 3T-L5H1-di6ii, l-Allyl-3,3-dihydroxy-5-phenyl-7-trifluoromethylll-ll,5-benzodiazepine-2,4-[ 3H,5H ]-dione,

7-ChloroQ3,3-dihydroxyl -methyl-5-(a-pyridyl)- l H-l,5-benzodiazepine-2,4-[ 3H,5H ]-dione,

3 ,3-Dihydroxyl -methyl-5-( m-trifluoromethyl-phenyl)-7-trifluoromethyll H- l ,5-benzodiazepine-2,4- [3H,5H1-dione, and

7-Chloro-3,3-dihydroxy-5-(o-trifluoromethyl-phenyl)- l H- l,5-benzodiazepine-2,4-[3H,5H l-dione.

The following examples further illustrate the present invention and willenable others skilled in the art to understand it more completely. Itshould be understood,

however, that the invention is not limited solely to the particularexamples given below.

EXAMPLE I 3,3-Dihydroxy-7-nitro-5-phenyl-1H-l,5-benzodiazepine-2,4-[3H,5H]-dione by method A 13.5 gm of3-(n-butylamino-methylidene)-7-nitro-5- phenyll H-],5-benzodiazepine-2,4-[ 3H,5l'l dione were dissolved in 2.3 liters ofwarm acetone, the resulting solution was acidified with dilute sulfuricacid, and then a solution of 18 gm ofpotassium permananate in 400 ml ofwater was added dropwise at a rate such that the temperature of themixture remained between 20 and C. Thereafter, the batch was allowed toreact for 3 to 4 hours more, was then vacuum-filtered through infusorialearth, and the filter cake was washed with acetone. The filtrate wasextracted twice with 2.5 liters of methylene chloride each, and thecombined extract solutions were dried with magnesium sulfate,vacuum-filtered and evaporated. The crystalline sub stance whichseparated out was collected by vacuum filtration and washed with coldmethylene chloride, yielding 5.7 gm (66.0 percent of theory) of thecompound of the formula having a melting point of l96 C (decomp.)

' EXAMPLE 2 7-Bromo-3,3-dihydroxy-5-phenyl-lH-1,5-benzodiazepine-2,4-[3H,5H]-dione by method A.

10 gm of 7-bromo-3-(n-butylamino-methylidene)-5-1phenyl-ll-l-l,5-benzodiazepine-2,4-[3H,5H]-dione were oxidized withpotassium permanganate in acetone as the solvent medium, in a manneranalogous to Example l. The raw product was recrystallized from acetone,yielding 6.2 gm (7] percent of theory) of the compound of the formulahaving a melting point F223C (decomp.).

EXAMPLE 3 7-Bromo-5-phenyl-l H-l ,5-benZodiazepine-2,3,4-

N-C (Julia having a melting point of 243 C (decomp.).

EXAMPLE 4 7-Bromo-3,3-dihydroxyl -methyl-5-phenyl-l l-l-l ,5-benzodiazepine-2,4-[3H,5H]-dione 4 gm of7-bromo-5-phenyl-ll-l-l,S-benzodiazepine- 2,3,4 [3H,5H1-trione (seepreceding example) were dissolved in 200 ml of acetone, 2. gm of sodiummethylate were added to the solution, and the resulting mixture'wasstirred for minutes. Thereafter, 12 ml of methyl iodide were added, andthe mixture was stirred at room temperature for 12 hours more.Subsequently, the reaction solution was evaporated in vacuo; theresidue, 7-bromol -methyl-5-phenyll H-l ,5-benzodiazepine-2,3,4-[3H,5l-l]-trione, was admixedwith water, and theaqueous mixture was extracted three times with ethyl acetate. Thecombined organic,

extracts were dried over magnesium sulfate and evaporated in vacuo, theresidue was recrystallized; from ether/isopropyl ether, and thevirtually pure productwas again recrystallized from tetrahydrofuran inthepresence of activated charcoal, yielding 2.7 gm (60 percent oftheory) of the compound of the formula 3 ,3-Dihydroxyl-methyl-5-phenyl-7-trifluoromethyllH-l,5-benzodiazepine-2,4-[3H,5H]-dioneby method A 1 aqueous mixture was vacuum-filtered, the filter cake waswashed with water and dissolved in ethyl acetate, the resulting solutionwas extracted with water, and the organic phase was dried over magnesiumsulfate and then vacuum-filtered through infusorial earth in thepresence of activated charcoal. The filtrate was then evaporated, andthe residue was recrystallized from a small amount of acetone/ether,yielding 4.0 hm (76 percent of theory) of the compound of the formulahaving a melting point of 164 1 66 C.

b. 4 gm of 3-(dimethylamino-methylidene)-lmethyl-5-phenyl-7-trifluoromethyl-1l-l-l,5-

benzodiazepine-2,4-[3H,5H]-dione were oxidized with 5 potassiumpermanganate in acetone, in a manner analogous to that described inExample 1. The reaction product crystallized with l mol of water ofcrystallization. 2.9 gm (77 percent of theory) of the compound of theformula were obtaine d, having a melting point'of 176 C (dec.)

I EXAMPLE 6 y "7 4 Chloro 3,3 dihydroxy-l methyl- 5 0 trifluoro z 5methyl-phenyl)- "-1- l ,5-benzodiazepine-2,4-[3H,5H]-

dione, by method B lo g m of 7-cliloro 3-hydro x y l rnethyl-5-(oltrifluoromethyl-phenyl l H-l ,5-benzodiazepine-2,4-[ 3 jH,5H]-dionewere dissolved in a mixture of 30 ml of 30 idimethylsulfoxide and 300 mlof ethyl acetate, gm of manganese dioxide were added to the solution,and the resulting mixture was stirred for 12 hours at room temperature.Thereafter, the reaction mixture was vacuum filtered, the filter cakewas washed with ethyl acetate, and the filtrate was extracted withwater. The organic phase was dried with magnesium sulfate and;evaporated in vacuo, and the residue was recrystallized? fromether/isopropyl ether, yielding 9.3 gm (89 percent? 0 of theory) of thecompound of the formula N--C=O NC =O having a melting point of 268-269C.

EXAMPLE 7 Using a procedure analogous to that described in Example 35-phenyl-7-trifluoromethyl- 1 1-1-1 ,5-

benzodiazepine-2,3,4-[3H,5H]-trione, m.p. 254 C (decomp.), of theformula ample Using a procedure analogous to that described in Examplel, 3,3-dihydroxy-5-phenyl-7-trifluoromethyl- 1H- 1,5-benzodiazepine-2,4-[3H,5H l-dione, m.p. 243245 C, of the formula fi vOH Flo OH l5 69. V was prepared from 3Kn butylamino-methylidene)-5-phenyl-7-trifluoromethyl-l l-ll ,S -benzodiazepine-ZA- [3H,51-d1one.

EXAMPLE 9' Using a procedure analogous to that described in Example 1,3,3-dihydroxy-5 phenyl-7-chl0ro-lH-l,5-benzodiazepine-2,4-[3H,5H]-dione, m.p. 190 C (decomp.), of the formula/o /N c/ 0H 01 c/ on nHa- 0 was rebEFTf'rdEF 3-( n-bu tglamino-methylidene )-5 phenyl-7-chlorol H-l ,5-benzodiazepine-2,4-[3H,5H 5

dione.

EXAMPLE 10 EXAMPLE I 1 Using a procedure analogous to, that described inEx- 6, l-isopropyl-3 ,3-dihydroxy-5 '-phenyl-7-trifluoromethyl-lH-1,5-benzodiazepine-2,4-[3H,5H]- dione, m.p. l77-l 78C, of the formula 8 was prepared from l-isopropyl-3-hydroxy-5-phenyl-7-trifluoromethyll H- 1 ,5 -benzodiazepine-2,4-[ 3H,5H.]- dione.

EXA PLE 12 I CIHa i N -c EXAMPLE l3 Using a procedure analogous to thatdescribed in Example 6, l-methyl-3,3-dihydroxy-5-(p-hydroxy-phenyl)-7-trifluoromethyl-l l-ll ,5-benzodiazepine-2,4-[ 3H, 5H]-dione, m.p.193 C (decomp.), of the formula was prepared froml-methyl-3-hydroxy-5-(p hydroxy-phenyl)-7-trifluoromethyll H-l ,5-

benzodiazepine-2,4-[3H,5H] dione.

EXAMPLE 14 Using a procedure analogous to that described in Example l,l-methyl-3,3-dihydroxy-j-(o nitro-phenyl)-7- dione, m.p. 177 C(decomp.), of the formula FIG was prepared froml-methyl-3-(n-butylamino-methyv EXAMPLE l8 lideneo-nitro-phenyl)-7-trifluoromethyll l-l-l ,5-

benzodiazepine 2,4 [3H5H] dione Using a procedure analogous to thatdescribed in Example l, l-methyl-3 ,3-dihydroxy-5-(m- EXAMPLE 1 5 5trifluoromethyl-phenyl-7-trifluoromethyll H- l ,5-

b n od' ine-2,4- 3H,5H -d'one, m. 130 C Using a procedure analogous tothat described in Exg z g i z the formula 1 l p ample 1,l-methyl-3,3-d1hydroxy-5-(a-pyr1dyl)-7- all M chloro-l l-l-l,5-benzodiazepine-2,4-[ 3l-l,5H]-dione, m.p. 165 C (decomp.), of theformula I (EH: 0/ N C=o FIG \O /OH \N C=/O H N-C=O 0H FAQ was preparedfrom l-methyl-3-( n-butylamino-methylidene)-5-(m-trifluoromethyl-phenyl)-7- was prepared from l-methyl-3-(d1methylam1no-methytrifluoromethyb 1H4 ,5 benzodiazepine 2,4 3H5H 1 lidene)-5-( a-pyridyl 7 -chloro-l H-1 ,5dione benzodiazepine-2,4- 3 H,5H] -dione.

EXAMPLE l6 Using a procedure analogous to that described in Ex- Usmg aprocedure analogous to that described m Example l 1 methyl 3,3 dihydroxys (m niuo phenyl) ample -P "Y 7-tri-fluoromethyl-l l-l-l,5-benzodiazepine-2,4-[3H, p -l -l n -P- 5l-l]-dione, m.p. 230 C(decomp.), of the formula C (decomp.), of the formula 25 EXAMPLE 19 H 7EH: %0

liked "0 0H 0H 3s C I 0 F10 01 on N--C=O OzN was prepared froml-H-3-(n-butylamino-methylidene)- was prepared f om 1- h ]-3-( -bm 1 i-fl -p y.5-benzodiazepinelidene)-5-(m-nitro-phenyl)-7-trifluoromethyl-lH-l ,5-

2,4-[3H,5H]-di0ne. benzodiazepine-2,4-[3H,5H]-dione.

EXAMPLE l7 EXAMPLE 20 Using a procedure analogous to tha C eS n Using aprocedure analogous to that described in Example 6,l-methyl-3,3-dihydroxy-5-(p-chloro-phenyD- ample l,3,3-dihydroxy-5-(o-trifluoromethyl-phenyl)- 7-tri-fl oro y l P 7-chlorolH-l ,5-benzodiazepine-2,4-[3H,5H ]-dione, 5l-ll-dione, m.p. 193 C(decomp.), of the formula m.p. l75l 76 C (decomp.), of the formula (EH1!V V H O --C=O H b z-0 Cl OH N-C I FaC was prepared froml-methyl-3-hydroxy-5-(p-chlorowas prepared from3-(n-butylamino-methylidene)-5- phenyl)-7-trifluoromethyll H- l,5-benzodiazepine-2,4- (o-trifluoromethyl-phenyl) 7-chloro-ll-l-l ,5- [3l-l,5 H l-dione. benzodiazepine-2,4-[ 3H,5 H ]-dione.

The compounds according to the present invention, that is, thoseembraced by formulas l and la above, have useful pharmacodynamicproperties. More particularly, the compounds of the instant inventionextion above referred to.

For pharmaceutical purposes the compounds according to the presentinvention are administered to warm-blooded animals perorally orparenterally as active ingredients in customary dosage unitcompositions, that is, compositions in dosage unit form consistingessentially of an inert pharmaceutical carrier and one effective dosageunit of the active ingredient, such as tablets, coated pills, capsules,wafers, powders, solutions, suspensions,,emulsions, syrups,suppositories and the like. One effective tranquilizing andanti-convulsive dosage unit of the compounds according to the presentinvention is from 0.0083 to 0.84-mgm/kg body weight, preferably 0.0166to 0.42 mgm/kg body weight, and the daily dose rate is 0.083 to2.5mgm/kg body weight.

The following examples illustrate a few pharmaceutical dosage unitcompositions comprising a compound of the present invention as an activeingredient and represent the best modes contemplated of putting theinvention into practical use. The parts are parts by weight unlessotherwise specified.

EXAMPLE 21 Coated pills I l The pill core composition is compounded fromthe following ingredients:

. l-Methyl-Ii ,3-dihydroxy- -phenyl7-bromo- 1 H-1 ,5-

benzodiazepine-2,4-[3H,5H]-dione 10.0 pans Lactose 37.5 Corn starch 25.0Gelatin 2.0 Magnesium stearate 0.5

Total 75.0 parts Preparation The benzodiazepine-dione compound isintimately admixed with the lactose and the corn starch, the mixture ismoistened with an aqueous l0 percentsolution of the gelatin, the moistmass is forced through a 1 mmmesh screen, the resulting granulate isdried at 40 C and again passed through the screen, the dry granulate isadmixed with the magnesium stearate, the composition is compressed into75 mgm-pill cores which are subsequently coated in conventional mannerwith a thin shell consisting essentially of a mixture of sugar,titaniumdioxide, talcum and gum arabic, and the coated pills arepolished with beeswax. Each pill contains l0 mgm of thebenzodiazepine-dione compound and is an oral dosage unit compositionwith effective tranquilizing and anticonvulsive actions.

The same result is obtained when the benzodiazepine-dione compound inthe above composition is replaced by one of the following compounds:

3 ,3-Dihydroxy-5-phenyl-7-b'romol H-l ,5-

benzodiazepine-2,4-[3H,5H1-dione; or7-Chloro-3,3-dihydroxy-l-methyl-5-(otrifluoromethyl-phenyl )-l H-l,S-benzodiazepine- EXAMPLE 22 Suppositories The suppository compositionis compounded from the following ingredients:

1700 parts Preparation The finely pulverized benzodiazepine-dionecompound is blended with the aid of an immersion homogenizer into thesuppository base which had previously been melted and cooled to 40 C.1700 mgm-portions of the composition are poured at 35 C into cooledsuppository molds and allowed to harden therein. Each suppositorycontains 15 mgm of the benzodiazepine-dione compound and is a rectaldosage unit composition with effective tranquilizing and anticonvulsiveactions.

Analogous results are obtained when any one of the otherbenzodiazepine-diones embraced by formula I or ananhydrous 2,3,4-trioneanalog of the formula la is substituted for the particularbenzodiazepine-dione in Examples 21 and 22. Likewise, the amount ofactive ingredient in these illustrative examples may be varied toachieve the dosage unit range set forth above, and the amounts andnature of the inert pharmaceutical carrier ingredients may be varied tomeet particular requirements.

While the present invention has been illustrated with the aid of certainspecific embodiments thereof, it will be readily apparent to othersskilled in the art that the invention is not limited to these particularembodiments, and that various changes and modifications may be madewithout departing from the spirit of the invention or the scope of theappended claims.

We claim:

1. A compound of the formula wherein R,', R and R have the meaningsdefined above. 2. A compound according to claim 1, wherein R is hydrogenor methyl, R is phenyl, o-fluoro-phen'yl trifluoromethylphenyl, and R ischlorine or bromine. 3. A compound according'to claim 2, which is 7-brom'o-3 ,3-dihydroxyl -m'ethyl-5 -phenyl- 1 1-1-1 ,5-benzodiazepine-2,4- 3H,5H -dione or 7-bromol l4methyl-S-phenyI-lH-l,5-benzodiazepine-2,3,4-[3H,5

4 H]-trione.

4. A compound according to claim 2, which is 7-bromo-Zi,3-dihydroxy-5-phenyl- 1 PH ,5-

' benzodiazepine-2,3,4-[3H,SH]-trione.

2. A compound according to claim 1, wherein R1 is hydrogen or methyl, R2is phenyl, o-fluoro-phenyl or o-trifluoromethylphenyl, and R3 ischlorine or bromine.
 3. A compound according to claim 2, which is7-bromo-3,3-dihydroxy-1-methyl-5-phenyl-1H-1,5-benzodiazepine-2,4-(3H,5H)-dione or7-bromo-1-methyl-5-phenyl-1H-1,5-benzodiazepine-2,3,4-(3H,5H)-trione. 4.A compound according to claim 2, which is7-bromo-3,3-dihydroxy-5-phenyl-1H-1,5-benzodiazepine-2,4-(3H,5H)-dioneor 7-bromo-5-phenyl-1H-1,5-benzodiazepine-2,3,4-(3H,5H)-trione.
 5. Acompound according to claim 2, which is7-bromo-3,3-dihydroxy-5-(o-fluoro-phenyl)-1-methyl-1H-1,5-benzodiazepine-2,4-(3H,5H)-dioneor7-bromo-5-(o-fluorophenyl)-1-methyl-1H-1,5-benzodiazepine-2,3,4-(3H,5H)-trione.
 6. A compound according to claim 2, which is7-chloro-3,3-dihydroxy-5-(o-trifluoromethyl-phenyl)-1H-1,5-benzodiazepine-2,4-(3H,5H)-dione or7-chloro-5-(o-trifluoromethyl-phenyl)-1H-1,5-benzodiazepine-2,3,4-(3H,5H)-trione.